Globally, over one hundred million people are exposed to elevated levels of inorganic arsenic from consuming contaminated drinking water. Although nutritional status may be a major determinant of individual susceptibility to arsenic and other toxicants, the impact of relevant nutrient levels in determining toxicological risks is rarel considered. Interestingly, arsenic contamination in the food supply and ground water also co-exists in many of the regions of the world that are prone to zinc deficiency. Zinc is an essential micronutrient important in growth and development, yet it has been estimated up to 82% of pregnant women worldwide have inadequate intakes of zinc. Zinc deficiency and arsenic exposures target similar mechanisms and both impact key developmental processes. In utero exposures to zinc deficiency and arsenic have both been associated with poor health outcomes including increased risk for metabolic syndrome and type 2 diabetes. However, the interactions between parental zinc deficiency and arsenic, and increased risk of developmental defects and associated mechanisms remain unclear. Our long-term goal is to identify diet-based susceptibility factors, such as zinc deficiency, that influence susceptibility to arsenic toxicity. Major barriers in identifying the mechanistic role of zinc during toxicological exposures is a lack of in vivo experimental models that allow us to directly study the effects of parental zinc on embryonic development. To overcome these barriers, we have chosen to use the premier vertebrate model for studying development, the zebrafish, because both early developmental processes and long term effects can be easily studied. Our central hypothesis is that in utero zinc deficiency sensitizes the developing embryo to low-dose arsenic toxicity leading to increased oxidative stress, inflammation and propensity to metabolic syndrome & diabetes development. Specifically, in aim 1, we will define developmental and mechanistic consequences of developmental zinc deficiency, arsenic exposures and their interaction related to development, pancreatic islet cell function, diabetes and metabolic syndrome. We will also identify targets such as oxidative stress and inflammation, as mechanisms by which zinc status alters sensitivity to arsenic-induced toxicities. In aim 2, we will identify contributing mechanism with a focus on Nrf2, a key regulator of the adaptive response to oxidative stress. The unique attributes of zebrafish provide a novel and innovative in vivo model to directly examine the effects of parental zinc status and developmental arsenic exposure on embryonic function and development of type 2 diabetes in vivo. Collectively these studies will aid in the identification o mechanisms by which parental nutrient deficits and early life exposure to toxicants affect the developing embryo and alters susceptibility to chronic disease later in life. This will ultimately help define nutritional strategies to improve health outcomes arsenic susceptible populations.